US9150585B2ActiveUtilityA1
Analogs of camptothecin
Est. expiryNov 13, 2032(~6.3 yrs left)· nominal 20-yr term from priority
Inventors:Qun Sun
C07D 491/22
83
PatentIndex Score
6
Cited by
3
References
28
Claims
Abstract
The present invention provides novel conjugates of camptothecin and camptothecin analogs with a linker and an HSA-binding moiety. The novel conjugates are prodrug forms of the camptothecin or camptothecin analogs and can be used to treat mammalian cell proliferative diseases, such as cancer.
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1. A compound of the following formula or a pharmaceutically acceptable salt thereof:
wherein
R 1 is OH or linker-HSA binding moiety;
R 2-6 are each, independently, H, halo, OH, NO 2 NH 2 , lower alkyl, O-lower alkyl, NH-lower alkyl, N(lower alkyl) 2 , lower alkyl-N(lower alkyl) 2 , lower alkyl-Si(lower alkyl) 3 ,
or linker-HSA binding moiety;
wherein
R 4 and R 5 optionally, together form —OCH 2 CH 2 O—,
R 2 and R 3 optionally, together form
and
if R 1 is OH, then at least one of R 2-6 must be linker-HSA binding moiety;
linker-HSA binding moiety is:
wherein
A is
R 7 is O, NH or a covalent bond;
R 9 is an unbranched or branched alkyl, alkylene or alkyne of 2 to 30 carbon atoms optionally including one or more ring structures of 3 to 6 atoms when R 9 has at least 7 carbon atoms, and including heteroatoms of oxygen in an integer number from 0 to one fifth the total number of carbon atoms in R 9 , with the proviso that there be no covalent bonds between oxygen atoms in R 9 ;
R 10 is, independently in each instance, H or lower alkyl;
R 13 is, independently in each instance, H, OH, NO 2 , NH 2 , NH 3 + , SH or a branched or unbranched alkyl, alkylene or alkyne of 1 to 8 carbon atoms, wherein the alkyl, alkylene or alkyne is optionally substituted with one or two substituents selected from the group consisting of halo, OH, NO 2 , NH 2 , NH 3 + , SH and ═O, and
optionally includes up to two heteroatoms independently selected from O, S and N, with the proviso that no O, S or N atom in the alkyl, alkylene or alkyne is covalently bonded to any other 0, S or N atom;
R 14 is, independently in each instance, H, OH, NO 2 , NH 2 , NH 3 + , SH or a branched or unbranched alkyl, alkylene or alkyne of 1 to 10 carbon atoms, wherein the alkyl, alkylene or alkyne optionally includes one or more ring structures of 3 to 9 atoms, is optionally substituted with one or two substituents selected from the group consisting of halo, OH, NO 2 , NH 2 , NH 3 + , SH and ═O, and
optionally includes up to two heteroatoms independently selected from O, S and N, with the proviso that no O, S or N atom in the alkyl, alkylene or alkyne is covalently bonded to any other O, S or N atom;
k is 0, 1 or 2;
m, independently in each instance, is 0, 1, 2 or 3;
n is 1, 2 or 3;
v is 0 or 1;
w is 0 or 1;
x is 0 or 1, with the proviso that x is 0 when a di-sulfide bond is present in A;
y is 0, 1, 2 or 3; and
z is 0 or 1
wherein the compound comprises no more than two linker-HSA binding moieties.
2. The compound of claim 1 , comprising one linker-HSA binding moiety.
3. The compound of claim 1 , comprising two linker-HSA binding moiety.
4. The compound of claim 1 , wherein linker-HSA binding moiety is:
5. The compound of claim 1 , wherein linker-HSA binding moiety is:
6. The compound of claim 1 , wherein linker-HSA binding moiety is:
7. The compound of claim 1 , wherein linker-HSA binding moiety is:
8. The compound of claim 1 , wherein linker-HSA binding moiety is:
9. The compound of claim 1 , wherein linker-HSA binding moiety is:
10. The compound of claim 1 , wherein linker-HSA binding moiety is:
11. The compound of claim 1 , wherein R 7 is a covalent bond.
12. The compound of claim 1 , wherein R 7 is O.
13. The compound of claim 1 , wherein R 7 is NH.
14. The compound of claim 1 , wherein R 2 is —CH 2 CH 3 ; R 3 is —H, R 4 is
R 5 is H; R 6 is H and R 1 is linker-HSA binding moiety.
15. The compound of claim 1 , wherein R 2 is H; R 3 is H; R 4 is H; R 5 is H; R 6 is H and R 1 is linker-HSA binding moiety.
16. The compound of claim 1 , wherein R 2 is H; R 3 is
R 4 is —OH or linker-HSA binding moiety; R 5 is H; R 6 is H; R 1 is —OH or linker-HSA binding moiety; at least one of R 1 and R 4 must be linker-HSA binding moiety.
17. The compound of claim 1 , wherein R 2 is —CH 2 CH 3 ; R 3 is H; R 4 is —OH or linker-HSA binding moiety; R 5 is H; R 6 is H; R 1 is —OH or linker-HSA binding moiety; at least one of R 1 and R 4 must be linker-HSA binding moiety.
18. The compound of claim 4 , wherein linker-HSA binding moiety is:
19. The compound of claim 8 , wherein linker-HSA binding moiety is:
20. The compound of claim 5 , wherein linker-HSA binding moiety is:
21. The compound of claim 14 , wherein linker-HSA binding moiety is:
22. The compound of claim 16 , wherein linker-HSA binding moiety is:
23. The compound of claim 17 , wherein linker-HSA binding moiety is:
24. A method to inhibit the enzyme topoisomerase I in an animal in need thereof, comprising administering to the animal an effective amount of a composition comprising a compound of claim 1 .
25. A method to treat cancer in a patient comprising administering a composition comprising a compound of claim 1 to said patient in an effective amount to treat said cancer.
26. The method of claim 25 , wherein said cancer is lung, breast, colon, prostate, melanoma, pancreas, stomach, liver, brain, kidney, uterus, cervix, ovaries, urinary tract, gastrointestinal or leukemia.
27. The method of claim 25 , wherein said cancer is solid tumor or blood borne tumor.
28. The method of claim 25 , wherein said composition is administered orally, parenterally, intramuscularly, transdermally, intravenously or by an airborne delivery system.Join the waitlist — get patent alerts
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